N-cyclopropyl-2-difluoromethoxy-3-halogenoanilines and intermediates for the preparation thereof

ABSTRACT

N-Cyclopropyl-2-difluoromethoxy-3-halogenoanilines which serve as important intermediates in the preparation of quinolonecarboxylic acids useful as synthetic antimicrobial agents from industrially inexpensive and easily available raw materials; and intermediates for the preparation thereof. Specifically, compounds represented by the general formula (1), (2) and (3),                    
     wherein X is halogeno; and Y is nitro or amino, (2) wherein X is halogeno; and R 1  is lower alkyl, (3) wherein X is halogeno; and R is hydrogen or —CH═C(CO 2 R 2 ) 2 , R 2  being lower alkyl.

TECHNICAL FIELD

The present invention relates to anN-cyclopropyl-2-difluoromethoxy-3-halogenoaniline and an intermediateused for production thereof.

BACKGROUND ART

In an international publication, WO 97/29102 is disclosed aquinolonecarboxylic acid having a cyclopropyl group at the 1-position,an isoindolinyl group at the 7-position and a difluoromethoxy group atthe 8-position, which is a synthetic antibacterial agent.

However, in the production method of the quinolonecarboxylic aciddescribed in the above laid-open patent publication, 2,6-difluoroanilinewhich is difficult to synthesize and procure industrially, must be usedas a starting material; many steps are employed; explosive sodium azideis used; and a diazotization step of low productivity is included. Thus,in carrying out the industrial production of the quinolonecarboxylicacid according to above method, there have been many problems in costand safety.

The present inventors made studies on the intermediate for thequinolonecarboxylic acid and the process for production thereof. As aresult, it was found out that by using a2-difluoromethoxy-3-halognonitrobenzene (which is a novel substance) asa raw material, reducing the compound to corresponding aniline,subjecting the aniline to cyclopropylation to synthesize anN-cyclopropylaniline, and reacting it with a dialkylalkoxymethylenemalonate typified by diethyl ethoxymethylenemalonate, acorresponding adduct was formed.

By subjecting the adduct to a ring-closing reaction according to a knownmethod, there can be easily derived a precursor of the above-mentionedquinolonecarboxylic acid, i.e. an alkyl1-cyclopropyl-4-oxo-7-halogeno-8-difluoro-methoxy-3-carboxylate.Therefore, it was confirmed that the above-mentioned intermediates(2-difluoromethoxy-3-halogenonitrobenzene, corresponding aniline andN-cyclopropylaniline) are important novel compounds in producing theabove quinolonecarboxylic acid derivative at a low cost according to anindustrially satisfactory method and are all easily synthesizedindustrially. Thus, the present invention has been completed.

DISCLOSURE OF THE INVENTION

The present invention provides a difluoromethoxybenzene derivativerepresented by the following formula (1):

wherein X is a halogen atom and Y is a nitro group or an amino group.

The present invention further provides anN-(1-alkoxycyclopropyl)-2-difluoromethoxy-3-halogenoaniline derivativerepresented by the following formula (2):

wherein X is a halogen atom and R¹ is a lower alkyl group; and anN-cyclopropyl-2-difluoromethoxy-3-halogenoaniline derivative representedby the following formula (3):

wherein X is a halogen atom and R is a hydrogen atom or a2,2-di(alkoxycarbonyl)ethylene group represented by the followingformula (4):

—CH═C(CO₂R²)₂  (4)

(wherein R² is a lower alkyl group).

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is described in detail below.

To obtain the final objective compound of the present invention, first,one of the objective compounds of the present invention, i.e. a2-difluoromethoxy-3-halogenonitrobenzene [a compound of the formula (1)wherein Y is a nitro group] is synthesized. As the raw materialtherefor, there can be used a 2-halogenophenol of good industrialavailability such as 2-chlorophenol, 2-bromophenol, 2-iodophenol or thelike. By nitrating the 2-halogenophenol according to a known method,there is obtained a 2-halogeno-6-nitrophenol such as2-cloro-6-nitrophenol, 2-bromo-6-nitrophenol, 2-iodo-6-nitrophenol orthe like.

In the above nitration, position isomers of nitro group are formed.However, an objective 2-halogeno-6-nitrophenol can be easily isolated ata high purity by using a purification means such as steam distillation,recrystallization or the like.

The 2-halogeno-6-nitrophenol can also be obtained by using ano-nitrophenol as a starting material and subjecting it to halogenation.Various other methods can also be used. In the present invention, thereis no restriction as to the method for obtaining the2-halogeno-6-nitrophenol.

Next, the 2-halogeno-6-nitrophenol is reacted with a difluoromethylationagent, for example, chlorodifluoromethane, whereby can be obtained a2-difluoromethoxy-3-halogenonitrobenzene [a compound of the formula (1)wherein Y is a nitro group], such as2-difluoromethoxy-3-chloronitrobenzene,2-difluoromethoxy-3-bromonitrobenzene,2-difluoromethoxy-3-iodonitrobenzene or the like.

The above difluoromethylation can be conducted by reacting the2-halogeno-6-nitrophenol with a difluoromethylation agent (e.g.chlorodifluoromethane) in the presence of a base. In this reaction,there may be used a solvent such as halogenated solvent (e.g.dichloromethane or dichloroethane), ether type solvent (e.g.1,4-dioxane, tetrahydrofuran, dimethoxyethane or diethylene glycoldimethyl ether), aprotic polar solvent (e.g. dimethylformamide,dimethylacetamide or dimethyl sulfoxide) or the like.

The temperature of the difluoromethylation must be room temperature orhigher. The reaction can be conducted in a temperature range up to theboiling point of the solvent used, at ordinary pressure. The reactionmay be conducted under a pressure which is generated spontaneously in aclosed vessel. The temperature is specifically from room temperature to150° C., preferably from 50 to 120° C.

The amount of the difluoromethylation agent (e.g. chlorodifluoromethane)used is 1 to 20 moles, preferably 1 to 5 moles per mole of the2-halogeno-6-nitrophenol. The base used can be exemplified by inorganicbases such as sodium hydroxide, potassium hydroxide, sodium carbonate,potassium carbonate and the like. Of these, sodium hydroxide, potassiumhydroxide or the like is preferred.

Incidentally, the difluoromethylation may be conducted in the presenceof a phase transfer catalyst such as tetra-n-butylammonium bromide,benzyltrimethylammonium chloride or the like.

Next, the above-obtained 2-difluoromethoxy-3-halogenonitrobenzene isreduced to obtain a 2-difluoromethoxy-3-halogenoaniline [a compound ofthe formula (1) wherein Y is an amino group], which is one objectivecompound of the present invention. A known technique can be used in thisreduction reaction.

There can be specifically used reduction using a metal (e.g. ironpowder, zinc or tin); catalytic reduction; reduction using a metalhydride (e.g. aluminum lithium hydride or sodium boron hydride); orreduction using a sulfur compound (e.g. sodium hydrosulfide or sodiumdithionite). Reduction using an iron powder is preferred.

The above-obtained 2-difluoromethoxy-3-halogenoaniline is subjected tocyclopropylation, whereby can be synthesized anN-cyclopropoyl-2-difluoromethoxy-3-halogenoaniline [a compound of theformula (3) wherein R is a hydrogen atom], which is one objectivecompound of the present invention. The cyclopropylation can be conductedby, as reported in J. Chem. Soc. Chem. Comm. 897 (1987), reacting the2-difluoromethoxy-3-halogenoaniline with 1-bromo-1-ethoxycyclopropaneand then reacting the reaction product with sodium boron hydride andboron trifluoride etherate.

Or, the cyclopropylation may be conducted by, as described inJP-A-10-87584, reacting the 2-difluoromethoxy-3-halogenoaniline with a1-alkoxy-1-trimethylsilyloxy-cyclopropane (e.g.1-ethoxy-1-trimethylsilyloxycyclopropane) in the presence of an organicacid (e.g. formic acid or acetic acid) or an inorganic acid (e.g.hydrochloric acid or sulfuric acid) in a straight chain or branchedchain alcohol type solvent having 1 to 6 carbon atoms, and then reducingthe reaction product with, for example, sodium boron hydride, preferablyin the presence of boron trifluoride etherate or the like.

Incidentally, when there is adopted, for example, the above-mentionedreaction of 2-difluoromethoxy-3-halogenoaniline with1-alkoxy-1-trimethylsilyloxycyclopropane (e g.1-ethoxy-1-trimethylsilyloxycyclopropane), there is derived anN-(1-alkoxycyclopropyl)-2-difluoromethoxy-3-halogenoaniline derivativerepresented by the formula (2):

which is one objective compound of the present invention.

In the above formula (2), X is a halogen atom, and R¹ is a lower alkylgroup, specifically a straight chain, branched chain or alicyclic alkylgroup having 1 to 6 carbon atoms. This R¹ may be converted into an alkylgroup derived from the solvent used, when there occurs solvent exchangein the reaction between 2-difluoromethoxy-3-halogenoaniline and1-alkoxy-1-trimethylsilyloxycyclopropane.

The thus-obtained N-cyclopropyl-2-difluoro-methoxy-3-halogenoaniline canbe converted, by reaction with an dialkyl alkoxymethylenemalonatetypified by diethyl ethoxymethylenemalonate, into a dialkylN-cyclo-propylanilinomethylenemalonate, i.e. a compound of the formula(3) wherein R is a residue represented by the following formula (4):

—CH═C(CO₂R²)₂  (4)

which is one objective compound of the present invention. In thisreaction, dealcoholation takes place simply by mixing and heating theN-cyclopropyl-2-difluoromethoxy-3-halogenoaniline and the dialkylalkoxymethylenemalonate, and an objective compound can be obtained at ahigh yield.

In the above formula (4), R² is a lower alkyl group, specifically astraight chain or branched chain alkyl group having 1 to 6 carbon atoms.Therefore, as the dialkyl alkoxymethylenemalonate usable in the abovereaction, there can be mentioned, for example, diethylethoxymethylenemalonate, diethyl methoxymethylenemalonate, dimethylmethoxymethylenemalonate, diethyl propoxymethylenemalonate, diethylbutoxymethylenemalonate, dimethyl ethoxymethylenemalonate, dipropylmethoxymethylenemalonate, dimethyl propoxymethylenemalonate and dibutylbutoxymethylenemalonate.

In the above reaction, the amount of the dialkyl alkoxymethylenemalonateused can be, for example, 1.0 to 10.0 moles, preferably 1.0 to 15.0moles per mole of the N-cyclopropyl-2-difluoromethoxy-3-halogenoaniline.

The thus-obtained dialkyl N-cyclopropylanilino-methylenemalonate [acompound of the formula (3) wherein R is a residue represented by theformula (4)] is easily subjected to ring closure by reaction withpolyphosphoric acid, polyphosphoric acid ester or the like according toa known method, and can be easily converted into a1-cyclopropyl-4-oxo-7-halogeno-8-difluoromethoxy-3-carboxylic acid esterwhich is an important precursor for a synthetic antibacterial agenthaving an isoindolinyl group at the 7-position.

EXAMPLES

Next, the present invention is described in more detail by way ofExamples.

Reference Example 1 Synthesis of 2-halogeno-6-nitrophenol

51.9 g (0.3 mol) of 2-bromophenol and 300 ml of acetic acid were fedinto a 1-liter four-necked flask provided with a reflux condenser, astirrer and a thermometer. Thereto was dropwise added 29.7 g (0.33 mol)of 70% nitric acid at a temperature of 15° C. or below, withice-cooling. The reaction mixture was stirred at a temperature of 10° C.or below for 1 hour and poured into 600 ml of water. The mixture wassubjected to extraction with 400 ml of ether. The ether layer was washedwith 150 ml of water. The ether layer was subjected to distillation. Theresidue was transferred into a 1-liter flask provided with a stirrer anda distillation apparatus. Azeotropic distillation was conducted whilewater was added gradually. The amount of water required for azeotropicdistillation was 2,100 ml. The distillate obtained was subjected toextraction two times using 500 ml of ether. The ether layer was driedover anhydrous sodium sulfate and subjected to distillation to removeether. The resulting crude product was mixed with 10 ml of ethanol. Themixture was heated and then allowed to cool. The formed crystals werecollected by filtration and then dried to obtain 22.3 g of2-bromo-6-nitrophenol (yield: 34.1%, purity: 99.6%).

Example 1

Into a 200-ml four-necked flask provided with a reflux condenser, astirrer and a thermometer were fed 4.36 g (0.02 mol) of2-bromo-6-nitrophenol, 16.7 g (0.1 mol) of 24% sodium hydroxide, 20 mlof 1,4-dioxane and 7 ml of water. The mixture was heated to 80° C. Themixture was stirred at that temperature for 11 hours with heating whilechlorodifluoromethane (flon 22) was blown thereinto from a bomb. Thereaction mixture was cooled and then subjected to extraction two timeseach using 20 ml of ether. The ether layer was washed with 20 ml of 12%sodium hydroxide and then with the same volume of water. Then, the etherlayer was dried over anhydrous sodium sulfate and then subjected todistillation to obtain 1.79 g of 3-bromo-2-difluoromethoxynitrobenzene(yield: 33.4%, purity: 98.8%). To the sodium hydroxide washing was addedhydrochloric acid to make the washing acidic, and the resultingprecipitate was subjected to extraction with ether, to recover 2.2 g ofunreacted 2-bromo-6-nitrophenol (recovery ratio: 50%).

Data obtained for 3-bromo-2-difluoromethoxynitrobenzene

Melting point: 43 to 45° C.

IR (KBr, cm⁻¹): 1520, 1350 (NO₂), 1040-1160 (CF₂)

Mass (m/e): 267, 269 (1:1, M⁺), 217, 219 (M⁺—CF₂), 200, 202 (M⁺—OCHF₂)

¹H-NMR (σ, CDCl₃): 6.60 (t, 1H, J=74 Hz, OCHF₂), 7.1-8.1(m, 3H, aromaticprotons)

Example 2

Into a 100-ml four-necked flask provided with a reflux condenser, astirrer and a thermometer were fed 0.95 g (17.0 mmol) of an iron powder,0.11 g (1.0 mmol) of 98% sulfuric acid, 15 ml of water and 1.62 g (6.0mmol) of 3-bromo-2-difluoromethoxynitrobenzene. The mixture was heatedon an oil bath and refluxed for 2 hours. After the completion of areaction, azeotropic distillation was conducted while 220 ml of waterwas added gradually. The distillate was subjected to extraction twotimes each using 100 ml of ether. The ether layer was dried overanhydrous sodium sulfate and then subjected to distillation. The residuewas distilled under vacuum to obtain 0.94 g of3-bromo-2-difluoromethoxyaniline (yield: 65.4%, purity: 98.5%).

Data obtained for 3-bromo-2-difluoromethoxyaniline

Boiling point: 135 to 140° C./9 mmHg (micro distillation, externaltemperature)

IR (neat, cm⁻¹): 3200-3500 (NH₂), 1000-1160 (CF₂)

Mass (m/e): 237, 239 (1:1, M⁺), 197, 199 (M⁺—2HF),187, 189 (M⁺—CF₂)

¹H-NMR (σ, CDCl₃): 3.6-4.7 (broad s, 2H, NH₂), 6.46 (t, 1H, J=75 Hz,OCHF₂), 6.5-7.2 (m, 3H, aromatic protons)

Example 3

Into a 50-ml three-necked flask provided with a reflux condenser, amagnetic stirrer and a thermometer were fed 0.88 g (3.7 mmol) of3-bromo-2-difluoromethoxyaniline, 0.75 g (4.4 mmol) of1-ethoxy-1-trimehtylsilyloxycyclopropane, 0.67 g (11.2 mmol) of aceticacid and 8 ml of methanol. The mixture was heated on an oil bath andrefluxed for 6 hours. Thereto was added 0.32 g (1.9 mmol) of1-ethoxy-1-trimethylsilyloxycyclopropane, followed by refluxing for 12hours. After completion of the reaction, methanol and acetic acid wereremoved by distillation under vacuum using a rotary evaporator, toobtain, as an oily substance, 1.00 g of1-(3-bromo-2-difluoromethoxy)anilino-1-methoxycyclopropane (yield:87.8%, purity: 92.3%).

Data obtained for1-(3-bromo-2-difluoromethoxy)anilino-1-methoxycyclopropane

Mass (m/e): 307, 309 (1:1, M⁺), 257, 259 (M⁺—CF₂)

¹H-NMR (σ, CDCl₃): 0.7-1.3 (4H, m, —CH₂CH₂), 3.26 (3H, S, OCH₃), 5.1-5.8(broad S, 1H,NH), 6.48 (t, 1H, J=75 Hz, OCHF₂), 6.7-7.4 (m, 3H, aromaticprotons)

Example 4

Into a 50-ml three-necked flask provided with a reflux condenser, amagnetic stirrer and a thermometer were fed 0.16 g (4.2 mmol) of sodiumboron hydride and 8 ml of anhydrous tetrahydrofuran. The flask insidewas purged with nitrogen, and the flask contents were ice-cooled.Thereto was dropwise added 0.6 g (4.2 mmol) of borontrifluoridetetrahydrofuran complex at 5° C. The reaction mixture wasstirred at 5° C. for 2 hours. Thereto was dropwise added, at the sametemperature, a solution of 1.00 g (3.3 mmol) of the crude1-(3-bromo-2-difluoromethoxy)anilino-1-methoxycyclopropane obtained inExample 3, dissolved in 2 ml of tetrahydrofuran. The mixture was heated,and stirred at room temperature for 1 hour and then at 60° C. for 2.5hours. Thereinto were fed 0.1 g (2.8 mmol) of sodium boron hydride and0.4 g (2.8 mmol) of boron trifluoride-tetrahydrofuran complex in thisorder, followed by stirring at 60° C. for 2 hours. The reaction mixturewas cooled and poured into water. The mixture was subjected toextraction two times each using 10 ml of ether. The residue wassubjected to distillation under vacuum to obtain 0.39 g ofN-cyclopropyl-2-difluoromethoxy-3-bromo-aniline (yield: 42.3%, purity:96.4%).

Data obtained for N-cyclopropyl-2-difluoromethoxy-3-bromo-aniline

Boiling point: 145-150° C./5 mmHg (micro distillation, externaltemperature)

IR (neat, cm⁻¹): 3450 (NH), 1000-1160 (CF₂)

Mass (m/e): 277, 279 (1:1, M⁺), 210, 212 (M⁺—CHF₂O)

¹H-NMR (σ, CDCl₃): 0.4-0.9 (4H, m, —CH₂CH₂), 2.1-2.7 (1H, m, NCH),4.5-4.8 (broad s, 1H, NH), 6.41 (t, 1H, J=75 Hz, OCHF₂), 6.7-7.4 (m, 3H,aromatic protons)

Example 5

Into a 25-ml round-bottomed flask provided with a distillation apparatusand a magnetic stirrer were fed 0.28 g (1.0 mmol) ofN-cyclopropyl-2-difluoromethoxy-3-bromoaniline obtained in Example 4 and1.08 g (5.0 mmol) of diethyl ethoxymethylenemalonate. The mixture wasstirred with heating on an oil bath of 140° C. for 30 minutes. Duringthe period, ethanol vaporized gradually. The oil bath temperature wasincreased to 160° C. and stirring was conducted for 1 hour. Then, thesame operation was conducted at 180° C. for 4.5 hours. The reactionmixture was cooled and subjected to column chromatography [packingmaterial: Wako Gel C-60, eluent: n-hexane/ethyl acetate (8:1)] to removecolored substances. Then, the solvent was removed by distillation toobtain 1.3 g of a light yellow oily substance. The oily substance wastransferred into a micro distillation apparatus and heated under vacuum(1 mmHg) on an oil bath of 140 to 150° C. to distil off unreacteddiethyl ethoxymethylenemalonate, whereby was obtained, as an oilyresidue, 180 mg of diethylN-cyclopropyl-2-difluoromethoxy-3-bromoanilinomethylenemalonate (yield:40.2%, purity: 97.6%).

Data obtained for diethylN-cyclopropyl-2-difluoromethoxy-3-bromoanilinomethylenemalonate

Mass (m/e): 449, 447 (1:1, M⁺)

¹H-NMR (σ, CDCl₃): 0.6-0.8 (4H, m, —CH₂CH₂), 1.08 (3H, t, J=7.0 Hz,CH₃), 1.25 (t, 3H, J=7.0 Hz, CH₃), 3.71 (q, 2H, J=7.0 Hz, CH₂), 4.10 (q,2H, J=7.0 Hz, CH₂), 6.65 (t, 1H, J=73 Hz, CHF₂), 7.64 (s, 1H, C═CH),6.9-7.5 (m, 2H, aromatic protons)

Example 6

Into a 1-liter four-necked flask provided with a reflux condenser, astirrer and a thermometer were fed 53.0 g (0.24 mol) of2-bromo-6-nitrophenol, 40.5 g (0.49 mol) of 48% sodium hydroxide, 240 mlof 1,3-dimethylimidazolidine-2-one and 40.5 g of water. The mixture washeated to 80° C. and stirred at the same temperature for 1.5 hours withheating while chlorodifluoromethane (flon 22) was blown thereinto from abomb. Then, while 20.0 g of 48% sodium hydroxide was added in sevenportions, blowing of flon gas was continued at the same temperature for7.5 hours. The total amount of flon gas blown was 242.3 g (2.80 mol).The reaction mixture was cooled. Thereto were added 26.0 g of 48% sodiumhydroxide, 1 liter of water and 500 ml of ether, and extraction andlayer separation was conducted. The organic layer was separated, and thewater layer was subjected to reextraction using 500 ml of ether. Theether layers were combined and washed with 500 ml of water two times.The resulting organic layer was dried over anhydrous sodium sulfate andsubjected to distillation to remove the solvent and obtain 45.4 g of3-bromo-2-difluoromethoxynitrobenzene (yield: 70.6%, purity: 98.1%).

Example 7

Into a 300-ml four-necked flask provided with a reflux condenser, astirrer and a thermometer were fed 6.56 g of an iron powder, 0.49 g (4.7mmol) of 95% sulfuric acid and 50 ml of water. The mixture was heated to80° C. on an oil bath. Thereto was slowly added, at 80 to 85° C., 12.54g (0.047 mol) of 3-bromo-2-difluoromethoxynitrobenzene. The temperaturewas increased and refluxing was conducted at 100° C. for 2 hours withheating. After completion of the reaction, azeotropic distillation wasperformed while 200 ml of water was added gradually. The distillate wassubjected to extraction two times each using 30 ml of dichloromethane.The organic layer was dried over anhydrous sodium sulfate and subjectedto distillation to remove the solvent and obtain 8.09 g of3-bromo-2-difluoromethoxyaniline (yield: 72.4%, purity: 99.7%).

Example 8

Into a 200-ml three-necked flask provided with a reflux condenser, amagnetic stirrer and a thermometer were fed 8.09 g (0.034 mol) of3-bromo-2-difluoromethoxyaniline, 8.54 g (0.049 mol) of1-ethoxy-1-trimethylsilyloxycyclopropane, 6.54 g (0.109 mol) of aceticacid and 36 ml of methanol. The mixture was heated on an oil bath andrefluxed for 10 hours. After the completion of a reaction, methanol andacetic acid were removed by distillation under vacuum using a rotaryevaporator to obtain, as a light yellow oily substance, 11.48 g of1-(3-bromo-2-difluoromethoxy)anilino-1-methoxycyclopropane.

Example 9

1.67 g (0.044 mol) of sodium boron hydride and 15 ml of anhydroustetrahydrofuran were fed into a 200-ml four-necked flask provided with areflux condenser, a stirrer and a thermometer. The flask inside waspurged with nitrogen and the flask contents were ice-cooled. Thereto wasdropwise added, at 5° C., 6.22 g (0.044 mmol) of borontrifluoridetetrahydrofuran complex. The reaction mixture was stirred at0 to 5° C. for 1 hour. Thereto was dropwise added, at 10 to 20° C., asolution of 11.48 g of the crude1-(3-bromo-2-difluoromethoxy)anilino-1-methoxycyclopropane obtained inExample 8, dissolved in 5 ml of toluene. The mixture was stirred at 50°C. for 2.5 hours and then at 60° C. for 15 hours.N-cyclopropyl-2-difluoromethoxy-3-bromoaniline (an objective compound)was formed by 50.5%.

1.93 g (0.051 mol) of sodium boron hydride and 15 ml of anhydroustetrahydrofuran were fed into a 50-ml three-necked flask provided with amagnetic stirrer and a thermometer as same as mentioned above. The flaskinside was purged with nitrogen and the flask contents were ice-cooled.Thereto was dropwise added, at 5° C., 7.04 g (0.050 mmol) of borontrifluoride-tetrahydrofuran complex. The reaction mixture was stirred at0 to 5° C. for 1 hour. The resulting mixture was added to theabove-obtained reaction mixture, followed by stirring at 60° C. for 24hours. The reaction mixture was cooled and poured into 200 ml of water.The mixture was stirred at room temperature for 2 hours and thensubjected to extraction using 200 ml of ether. The ether layer was driedover anhydrous sodium sulfate and subjected to distillation to removethe solvent and obtain 10.17 g of a colorless oily substance. Thissubstance was subjected to distillation under vacuum to obtain 7.82 g ofN-cyclopropyl-2-difluoromethoxy-3-bromoaniline (yield: 82.7% relative tothe raw material used in Example 8, purity: 95.4%).

Example 10

Into a 50-ml round-bottomed flask provided with a distillation apparatusand a magnetic stirrer were fed 3.33 g (0.012 mol) ofN-cyclopropyl-2-difluoromethoxy-3-bromoaniline and 3.11 g (0.0144 mol)of diethyl ethoxymethylenemalonate. The mixture was stirred on an oilbath at 150° C. for 1.5 hours. During this period, ethanol vaporizedgradually. The reaction temperature was increased to 170° C., andstirring was conducted for 13.5 hours while nitrogen gas was blownthereinto. The reaction mixture was cooled to obtain a brown oilysubstance. This substance was analyzed by gas chromatography. As aresult, the substance contained 10.8% (by areal percentage) of diethylethoxymethylenemalonate and 86.6% of, as an objective compound, diethylN-cyclopropyl-2-difluoromethoxy-3-bromoanilinomethylenemalonate.

Reference Example 2

26 g of polyphosphoric acid was fed into a 200-ml four-necked flaskprovided with a reflux condenser, a stirrer and a thermometer. Themixture was heated to 60° C. Thereto was dropwise added, at 55 to 60°C., the crude diethylN-cyclopropyl-2-difluoromethoxy-3-bromoanilinomethylenemalonate obtainedin Example 10, dissolved in 0.8 g of toluene. The mixture was heatedwith stirring, and stirred at 90 to 95° C. for 2 hours. The reactionmixture was cooled and poured into 100 ml of water, and the mixture wasstirred for 1 hour. The resulting crystals were collected by filtration,washed with water, and dried to obtain 3.98 g of crude crystals. 30 mlof ethanol was added to the crude crystals. The mixture was refluxedwith heating, cooled and filtered. The collected substance was dried toobtain 2.12 g of ethyl7-bromo-1-cyclopropyl-8-difluoromethoxy-4-oxo-1,4-dihydro-3-quinoline-carboxylate(yield: 43.9% relative to the raw material used in Example 10). Themelting point was 252.6° C.

The IR and NMR spectrum of the obtained compound agreed with thosedescribed in the patent publication, WO 97/29102.

Industrial Applicability

As described above, the present invention provides, from ahalogenophenol or a nitrophenol (each is a raw material which isindustrially inexpensive and easy to procure), ann-cyclopropyl-2-difluoromethoxy-3-halogenianiline which is a novelsubstance not described in any literature and which is an importantintermediate for producing, industrially and at a low cost, a syntheticantibacterial agent having an isoindolinyl group, a cyclopropyl groupand a difluoromethoxy group; and an intermediate used for productionthereof.

What is claimed is:
 1. A difluoromethoxybenzene derivative representedby the following formula (1):

wherein X is a halogen atom and Y is a nitro group or an amino group. 2.An N-(1-alkoxycyclopropyl)-2-difluoromethoxy-3-halogenoanilinederivative represented by the following formula (2):

wherein X is a halogen atom and R¹ is a lower alkyl group.
 3. AnN-cyclopropyl-2-difluoromethoxy-3-halogenoaniline derivative representedby the following formula (3):

wherein X is a halogen atom and R is a hydrogen atom or a2,2-di(alkoxycarbonyl)ethylene group represented by the followingformula (4): —CH═C(CO₂R²)₂  (4) (wherein R² is a lower alkyl group).